Liver stiffness predicts progression to liver-related events in patients with chronic liver disease - A cohort study of 14 414 patients.

BACKGROUND & AIMS: Liver stiffness measurement (LSM) by vibration-controlled transient elastography (VCTE) is a non-invasive diagnostic biomarker of liver fibrosis. It is uncertain if LSM can predict risk for future liver-related outcomes in large, heterogenous populations. METHODS: This Swedish multi-centre cohort study included patients (n = 14 414) from 16 sites who underwent LSM by VCTE between 2008 and 2020. Outcomes were ascertained from national registers. We investigated progression to cirrhosis with portal hypertension or hepatocellular carcinoma (HCC), separately. Cox regression was used to obtain hazard ratios (HRs). Harrel's C-index was used to measure discrimination of VCTE. RESULTS: Included patients had a median age of 46 (interquartile range 34-57), median LSM of 5.9 kPa (4.6-8.0), 59% were male, and the majority had hepatitis C (50.1%). During a median follow-up of 5.9 (4.3-8.0) years, 402 patients (2.7%) developed cirrhosis with portal hypertension. In patients with an LSM ≥25 kPa, 28.7% developed cirrhosis with portal hypertension within 5 years of follow-up, while only .6% of patients with an LSM <10 kPa did. This translated to a HR of 48.3 (95% confidence interval = 37.6-62.0). VCTE had a high discriminative ability, with C-indices above .80 for most liver diseases, including .82 for MASLD. Similar findings were seen for incident HCC. CONCLUSIONS: Increased LSM by VCTE was associated with an increased risk of progression to both cirrhosis with portal hypertension, and to HCC, and had a high discriminative ability across different aetiologies of chronic liver diseases. These results support the use of VCTE to guide follow-up and treatment decisions.

Complex norovirus transmission dynamics at hospital wards revealed by deep sequencing.

Detailed knowledge regarding norovirus transmission within hospitals is limited. We investigated a norovirus hospital outbreak affecting 65 patients at five different wards. PCR showed that 61 (94%) of the patients were infected with genotype II.4 strains. Successful Ion Torrent deep sequencing of GII.4 positive samples from 59 patients followed by phylogenetic analysis revealed that all sequences but two clustered into four distinct clades. Two of the clades belonged to GII.4 Sydney 2012, while the other two belonged to GII.4 New Orleans 2009. One of the clades was predominant at two wards, while two clades were predominant at one ward each. The fourth clade was found in sporadic cases at several wards. Thus, at four out of five wards, variants from one clade were predominant. At one ward, a single clade accounted for all cases, while at three wards the predominant clade accounted for 60%-71% of cases. Analysis of quasispecies variation identified positions that could further discriminate between variants from separate wards. The results illustrate a complex transmission of healthcare-associated norovirus infections and show that sequencing can be used to discriminate between related and unrelated cases.

Teasing apart the joint effect of demography and natural selection in the birth of a contact zone.

Vast population movements induced by recurrent climatic cycles have shaped the genetic structure of plant species. During glacial periods species were confined to low-latitude refugia from which they recolonized higher latitudes as the climate improved. This multipronged recolonization led to many lineages that later met and formed large contact zones. We utilize genomic data from 5000 Picea abies trees to test for the presence of natural selection during recolonization and establishment of a contact zone in Scandinavia. Scandinavian P. abies is today made up of a southern genetic cluster originating from the Baltics, and a northern one originating from Northern Russia. The contact zone delineating them closely matches the limit between two major climatic regions. We show that natural selection contributed to its establishment and maintenance. First, an isolation-with-migration model with genome-wide linked selection fits the data better than a purely neutral one. Second, many loci show signatures of selection or are associated with environmental variables. These loci, regrouped in clusters on chromosomes, are often related to phenology. Altogether, our results illustrate how climatic cycles, recolonization and selection can establish strong local adaptation along contact zones and affect the genetic architecture of adaptive traits.

System dynamic modelling of healthcare associated influenza -a tool for infection control.

BACKGROUND: The transmission dynamics of influenza virus within healthcare settings are not fully understood. Capturing the interplay between host, viral and environmental factors is difficult using conventional research methods. Instead, system dynamic modelling may be used to illustrate the complex scenarios including non-linear relationships and multiple interactions which occur within hospitals during a seasonal influenza epidemic. We developed such a model intended as a support for health-care providers in identifying potentially effective control strategies to prevent influenza transmission. METHODS: By using computer simulation software, we constructed a system dynamic model to illustrate transmission dynamics within a large acute-care hospital. We used local real-world clinical and epidemiological data collected during the season 2016/17, as well as data from the national surveillance programs and relevant publications to form the basic structure of the model. Multiple stepwise simulations were performed to identify the relative effectiveness of various control strategies and to produce estimates of the accumulated number of healthcare-associated influenza cases per season. RESULTS: Scenarios regarding the number of patients exposed for influenza virus by shared room and the extent of antiviral prophylaxis and treatment were investigated in relation to estimations of influenza vaccine coverage, vaccine effectiveness and inflow of patients with influenza. In total, 680 simulations were performed, of which each one resulted in an estimated number per season. The most effective preventive measure identified by our model was administration of antiviral prophylaxis to exposed patients followed by reducing the number of patients receiving care in shared rooms. CONCLUSIONS: This study presents an system dynamic model that can be used to capture the complex dynamics of in-hospital transmission of viral infections and identify potentially effective interventions to prevent healthcare-associated influenza infections. Our simulations identified antiviral prophylaxis as the most effective way to control in-hospital influenza transmission.

Presence of interferon-λ 4, male gender, absent/mild steatosis and low viral load augment antibody levels to hepatitis C virus.

OBJECTIVES: Despite recombinant interferon-λ 4 (IFN-λ4) demonstrating anti-viral activity in vitro and the ancestral functional gene (IFNL4) being conserved in all other primates, there has been speculation that IFN-λ4 may be detrimental in humans. In light of recent rekindled interest in humoral immunity, this study aimed at evaluating the impact of baseline characteristics, including IFNL4, on antibody levels to hepatitis C virus (HCV). MATERIALS AND METHODS: Pretreatment sera from 279 well-characterized North European Caucasians with chronic HCV genotype 2 or 3 infection having undergone liver biopsy were analyzed regarding IFNL4 (rs12979860) and anti-HCV antibody levels using a commercially available assay. RESULTS: Patients producing IFN-λ4 had higher signal to cut-off (S/CO) anti-HCV antibody ratios as compared with those lacking IFN-λ4 (IFNL4rs12979860 CT/TT versus CC, p<.0001, Mann-Whitney U-test). Additionally, in univariate analyses S/CO was significantly higher in men than women (p<.001), as well as in patients with absent/mild interface hepatitis (Ishak grade 0-2 versus 3-4, p = .009), and absent/mild steatosis (grade 0-1 versus 2-3, p = .0005). Also, an inverse correlation with HCV RNA level (rs= -0.14, p = .02) was noted. In multivariate analysis IFN-λ4, gender, steatosis and viral load remained independently associated. CONCLUSIONS: To our knowledge, this is the first report that demonstrates that the ability to produce IFN-λ4, in addition to male gender, absent/mild steatosis, and lower viral load, augments antibody levels against HCV. This indicates that IFN-λ4 may be associated with T helper cell 2 (Th2) immune skewing, which might have clinical implications beyond HCV infection. ClinicalTrials.gov Identifier: NCT00143000.

Does C-reactive protein predict time to recovery and benefit from oseltamivir treatment in primary care patients with influenza-like illness? A randomized controlled trial secondary analysis.

OBJECTIVE: Recovery time and treatment effect of oseltamivir in influenza-like illness (ILI) differs between patient groups. A point-of-care test to better predict ILI duration and identify patients who are most likely to benefit from oseltamivir treatment would aid prescribing decisions in primary care. This study aimed to investigate whether a C-reactive protein (CRP) concentration of ≥30 mg/L can predict (1) ILI disease duration, and (2) which patients are most likely to benefit from oseltamivir treatment. DESIGN: Secondary analysis of randomized controlled trial data. SETTING: Primary care in Lithuania, Sweden and Norway during three consecutive influenza seasons 2016-2018. SUBJECTS: A total of 277 ILI patients aged one year or older and symptom duration of ≤72 h. MAIN OUTCOME MEASURES: Capillary blood CRP concentration at baseline, and ILI recovery time defined as having 'returned to usual daily activity' with residual symptoms minimally interfering. RESULTS: At baseline, 20% (55/277) had CRP concentrations ≥30mg/L (range 0-210). CRP concentration ≥30 mg/L was not associated with recovery time (adjusted hazards ratio (HR) 0.80: 95% CI 0.50-1.3; p = 0.33). Interaction analysis of CRP concentration ≥30 mg/L and oseltamivir treatment did not identify which patients benefit more from oseltamivir treatment (adjusted HR 0.69: 95% CI 0.37-1.3; p = 0.23). CONCLUSION: There was no association between CRP concentration of ≥30 mg/L and recovery time from ILI. Furthermore, CRP could not predict which ILI patients benefit more from oseltamivir treatment. Hence, we do not recommend CRP testing for predicting ILI recovery time or identifying patients who will receive particular benefit from oseltamivir treatment.Key PointsPredicting disease course of influenza-like illness (ILI), and identifying which patients benefit from oseltamivir treatment is a challenge for physicians.• There was no association between CRP concentration at baseline and recovery time in patients consulting with ILI in primary care.• There was no association between CRP concentration at baseline and benefit from oseltamivir treatment.• We, therefore, do not recommend CRP testing for predicting recovery time or in decision-making concerning oseltamivir prescribing in ILI patients.

Extensive Hospital In-Ward Clustering Revealed By Molecular Characterization of Influenza A Virus Infection.

BACKGROUND: Nosocomial transmission of influenza A virus (InfA) infection is not fully recognized. The aim of this study was to describe the characteristics of hospitalized patients with InfA infections during an entire season and to investigate in-ward transmission at a large, acute-care hospital. METHODS: During the 2016-17 season, all hospitalized patients ≥18 years old with laboratory-verified (real-time polymerase chain reaction) InfA were identified. Cases were characterized according to age; sex; comorbidity; antiviral therapy; viral load, expressed as cycle threshold values; length of hospital stay; 30-day mortality; and whether the InfA infection met criteria for a health care-associated influenza A infection (HCAI). Respiratory samples positive for InfA that were collected at the same wards within 7 days were chosen for whole-genome sequencing (WGS) and a phylogenetic analysis was performed to detect clustering. For reference, concurrent InfA strains from patients with community-acquired infection were included. RESULTS: We identified a total of 435 InfA cases, of which 114 (26%) met the HCAI criteria. The overall 30-day mortality rate was higher among patients with HCAI (9.6% vs 4.6% among non-HCAI patients), although the difference was not statistically significant in a multivariable analysis, where age was the only independent risk factor for death (P < .05). We identified 8 closely related clusters (involving ≥3 cases) and another 10 pairs of strains, supporting in-ward transmission. CONCLUSIONS: We found that the in-ward transmission of InfA occurs frequently and that HCAI may have severe outcomes. WGS may be used for outbreak investigations, as well as for evaluations of the effects of preventive measures.

Pollen exposure weakens innate defense against respiratory viruses.

BACKGROUND: Hundreds of plant species release their pollen into the air every year during early spring. During that period, pollen allergic as well as non-allergic patients frequently present to doctors with severe respiratory tract infections. Our objective was therefore to assess whether pollen may interfere with antiviral immunity. METHODS: We combined data from real-life human exposure cohorts, a mouse model and human cell culture to test our hypothesis. RESULTS: Pollen significantly diminished interferon-λ and pro-inflammatory chemokine responses of airway epithelia to rhinovirus and viral mimics and decreased nuclear translocation of interferon regulatory factors. In mice infected with respiratory syncytial virus, co-exposure to pollen caused attenuated antiviral gene expression and increased pulmonary viral titers. In non-allergic human volunteers, nasal symptoms were positively correlated with airborne birch pollen abundance, and nasal birch pollen challenge led to downregulation of type I and -III interferons in nasal mucosa. In a large patient cohort, numbers of rhinoviruspositive cases were correlated with airborne birch pollen concentrations. CONCLUSION: The ability of pollen to suppress innate antiviral immunity, independent of allergy, suggests that high-risk population groups should avoid extensive outdoor activities when pollen and respiratory virus seasons coincide.

PCR Detection of Respiratory Pathogens in Asymptomatic and Symptomatic Adults.

The frequency of viral respiratory pathogens in asymptomatic subjects is poorly defined. The aim of this study was to explore the prevalence of respiratory pathogens in the upper airways of asymptomatic adults, compared with a reference population of symptomatic patients sampled in the same centers during the same period. Nasopharyngeal (NP) swab samples were prospectively collected from adults with and without ongoing symptoms of respiratory tract infection (RTI) during 12 consecutive months, in primary care centers and hospital emergency departments, and analyzed for respiratory pathogens by a PCR panel detecting 16 viruses and four bacteria. Altogether, 444 asymptomatic and 75 symptomatic subjects completed sampling and follow-up (FU) at day 7. In the asymptomatic subjects, the detection rate of viruses was low (4.3%), and the most common virus detected was rhinovirus (3.2%). Streptococcus pneumoniae was found in 5.6% of the asymptomatic subjects and Haemophilus influenzae in 1.4%. The only factor independently associated with low viral detection rate in asymptomatic subjects was age ≥65 years (P = 0.04). An increased detection rate of bacteria was seen in asymptomatic subjects who were currently smoking (P < 0.01) and who had any chronic condition (P < 0.01). We conclude that detection of respiratory viruses in asymptomatic adults is uncommon, suggesting that a positive PCR result from a symptomatic patient likely is relevant for ongoing respiratory symptoms. Age influences the likelihood of virus detection among asymptomatic adults, and smoking and comorbidities may increase the prevalence of bacterial pathogens in the upper airways.

Muscle performance and fatigue in compensated chronic liver disease.

Background: A common and debilitating symptom in patients with chronic liver disease is fatigue (CLD). Muscle dysfunction has been suggested to be a key mechanism of fatigue in CLD. Objective: We aimed to evaluate fatigue and the potential association with muscle performance and physical activity in outpatients with CLD. Methods: Two-hundred seventy outpatients with CLD were included, (52 ± 15 years, mean ± SD; 151 females) with autoimmune hepatitis (n = 49), primary biliary cholangitis (n = 45), primary sclerosing cholangitis (n = 46), chronic hepatitis B (n = 57) or C (n = 73). Patients with a Child-Pugh >6 were excluded. The questionnaire Fatigue Impact Scale (FIS) was used to evaluate fatigue, and physical activity was evaluated through a self-reported level of physical activity. Muscle function was assessed with four muscle tests, walking speed, handgrip strength, standing heel-rise test (SHT) and 'Timed Up and Go' test (TUG). Results: The median total FIS score was 30 (40% had FIS > 40, considered high-fatigue). Diminished muscle performance was observed in the SHT (% of predicted value: 53 ± 26%) and with maximum grip strength (85 ± 20%). The FIS score was significantly different between groups of CLDs (p = .004). In multivariate analysis the TUG (p = .001), SHT (p = .005), antidepressants (p < .001), and level of physical activity (p = .001) were associated with fatigue (R2 = 29%). Subjects with higher levels of physical activity had lower FIS (p < .001). Conclusions: In patients with CLD, fatigue was associated with low muscle performance and reduced level of physical activity, which could be a potential therapeutic target.

Increased Prediction Ability in Norway Spruce Trials Using a Marker X Environment Interaction and Non-Additive Genomic Selection Model.

A genomic selection study of growth and wood quality traits is reported based on control-pollinated Norway spruce families established in 2 Northern Swedish trials at 2 locations using exome capture as a genotyping platform. Nonadditive effects including dominance and first-order epistatic interactions (including additive-by-additive, dominance-by-dominance, and additive-by-dominance) and marker-by-environment interaction (M×E) effects were dissected in genomic and phenotypic selection models. Genomic selection models partitioned additive and nonadditive genetic variances more precisely than pedigree-based models. In addition, predictive ability in GS was substantially increased by including dominance and slightly increased by including M×E effects when these effects are significant. For velocity, response to genomic selection per year increased up to 78.9/80.8%, 86.9/82.9%, and 91.3/88.2% compared with response to phenotypic selection per year when genomic selection was based on 1) main marker effects (M), 2) M + M×E effects (A), and 3) A + dominance effects (AD) for sites 1 and 2, respectively. This indicates that including M×E and dominance effects not only improves genetic parameter estimates but also when they are significant may improve the genetic gain. For tree height, Pilodyn, and modulus of elasticity (MOE), response to genomic selection per year improved up to 68.9%, 91.3%, and 92.6% compared with response to phenotypic selection per year, respectively.Subject Area: Quantitative genetics and Mendelian inheritance.

Measles outbreak in Gothenburg urban area, Sweden, 2017 to 2018: low viral load in breakthrough infections.

In an outbreak of measles in Gothenburg, Sweden, breakthrough infections (i.e. infections in individuals with a history of vaccination) were common. The objective of this study was to compare measles RNA levels between naïve (i.e. primary) and breakthrough infections. We also propose a fast provisional classification of breakthrough infections. Medical records were reviewed and real-time PCR-positive samples genotyped. Cases were classified as naïve, breakthrough or vaccine infections. We compared clinical symptoms and measles RNA cycle threshold (Ct) values between breakthrough and naïve infections. Sixteen of 28 confirmed cases of measles in this outbreak were breakthrough infections. A fast provisional classification, based on previous history of measles vaccination and detectable levels of measles IgG in acute serum, correctly identified 14 of the 16 breakthrough infections, confirmed by IgG avidity testing. Measles viral load was significantly lower in nasopharyngeal samples from individuals with breakthrough compared with naïve infections (median Ct-values: 32 and 19, respectively, p < 0.0001). No onward transmission from breakthrough infections was identified. Our results indicate that a high risk of onward transmission is limited to naïve infections. We propose a fast provisional classification of breakthrough measles that can guide contact tracing in outbreak settings.

Accuracy of genomic selection for growth and wood quality traits in two control-pollinated progeny trials using exome capture as the genotyping platform in Norway spruce.

BACKGROUND: Genomic selection (GS) can increase genetic gain by reducing the length of breeding cycle in forest trees. Here we genotyped 1370 control-pollinated progeny trees from 128 full-sib families in Norway spruce (Picea abies (L.) Karst.), using exome capture as genotyping platform. We used 116,765 high-quality SNPs to develop genomic prediction models for tree height and wood quality traits. We assessed the impact of different genomic prediction methods, genotype-by-environment interaction (G × E), genetic composition, size of the training and validation set, relatedness, and number of SNPs on accuracy and predictive ability (PA) of GS. RESULTS: Using G matrix slightly altered heritability estimates relative to pedigree-based method. GS accuracies were about 11-14% lower than those based on pedigree-based selection. The efficiency of GS per year varied from 1.71 to 1.78, compared to that of the pedigree-based model if breeding cycle length was halved using GS. Height GS accuracy decreased to more than 30% while using one site as training for GS prediction and using this model to predict the second site, indicating that G × E for tree height should be accommodated in model fitting. Using a half-sib family structure instead of full-sib structure led to a significant reduction in GS accuracy and PA. The full-sib family structure needed only 750 markers to reach similar accuracy and PA, as compared to 100,000 markers required for the half-sib family, indicating that maintaining the high relatedness in the model improves accuracy and PA. Using 4000-8000 markers in full-sib family structure was sufficient to obtain GS model accuracy and PA for tree height and wood quality traits, almost equivalent to that obtained with all markers. CONCLUSIONS: The study indicates that GS would be efficient in reducing generation time of breeding cycle in conifer tree breeding program that requires long-term progeny testing. The sufficient number of trees within-family (16 for growth and 12 for wood quality traits) and number of SNPs (8000) are required for GS with full-sib family relationship. GS methods had little impact on GS efficiency for growth and wood quality traits. GS model should incorporate G × E effect when a strong G × E is detected.

Genetic variation in IL28B (IFNL3) and response to interferon-alpha treatment in myeloproliferative neoplasms.

OBJECTIVE: In myeloproliferative neoplasms (MPN), interferon-alpha (IFN-α) is an effective treatment with disease-modifying properties but currently with no clear predictors of treatment outcome. Recent genomewide association studies in chronic hepatitis C have found a strong influence of genetic polymorphism near the IL28B (IFNL3) gene in response to IFN-α treatment. In this study, we sought to evaluate the prognostic impact of IL28B rs12979860, rs8099917, and rs12980275 on IFN-α treatment response in myeloproliferative neoplasms. METHOD: We retrospectively evaluated 100 patients with MPN treated with IFN-α. The hematologic treatment response on IFN-α was compared between patients and correlated with host genetic variations in IL28B. The genotypes of IL28B were determined by allelic discrimination assays. RESULTS: The CC genotype of rs12979860 was found significantly associated with hematologic response in polycythemia vera (PV) with a complete response (CR) in 79% (CC) compared to 48% (non-CC), (P = .036). No association between the genotypes and treatment response on hydroxyurea was found. CONCLUSION: These results imply an effect of IL28B genotype on the outcome of IFN-α treatment in MPN.

Slow Clearance of Norovirus following Infection with Emerging Variants of Genotype GII.4 Strains.

The emergence of new norovirus genotype GII.4 strains is associated with widespread norovirus epidemics. Extended periods of viral shedding can contribute to the epidemic potential of norovirus. To describe the duration of viral shedding in infections with novel emerging GII.4 strains versus infections with previously circulating strains, we performed a prospective cohort study of patients hospitalized with norovirus gastroenteritis during separate winter seasons. Rectal swab samples were obtained at the time of inclusion and weekly during follow-ups. The subgenotype strain was determined from capsid sequences. The outcome was defined by the detection of virus for >14 days (slow clearance) or by the detection of negative samples within 14 days (rapid clearance). Two major epidemic GII.4 strains emerged during the study period, GII.4 New Orleans 2009, in 2010, and GII.4 Sydney 2012, in 2012. From these two seasons, sequences were available from 24 cases where the duration of shedding could be determined. The median age of the patients was 83 years and 50% were women. The majority of patients were infected with virus that clustered with the respective season's epidemic strain (n = 19), whereas 5 patients had previously circulating strains (3 were Den Haag 2006b, in 2010, and 2 were New Orleans 2009, in 2012). Among the patients infected with an epidemic strain, the proportion who shed virus for >14 days was significantly higher (16/19 [84%] versus 1/5 [20%], P = 0.01). In summary, a slow clearance of norovirus from stool was more common in infections with novel epidemic GII.4 strains. This suggests that the average duration of shedding may be longer during seasons when new GII.4 strains have emerged.

Short interferon and ribavirin treatment for HCV genotype 2 or 3 infection: NORDynamIC trial and real-life experience.

OBJECTIVE: Interferon-free therapy for hepatitis C virus (HCV) infection is costly, and therefore patients with advanced fibrosis are prioritized. Although coupled with considerable side effects, a large proportion of genotype 2/3 infected patients achieve a sustained virological response (SVR) following interferon-based therapy. The present study evaluates experimental clinical trial and verifying real-life data with the aim of identifying patients with a high likelihood of favorable outcome following short interferon-based treatment. MATERIAL AND METHODS: The impact of established response predictors, e.g. age, ITPA and IL28B genetic variants, IP-10, liver histopathology and early viral kinetics on outcome was evaluated among HCV genotype 2/3 infected patients enrolled in the NORDynamIC trial. Similarly outcome was evaluated among Finnish and Swedish real-life genotype 2/3 infected patients treated for 12-16 weeks in accordance with national guidelines. RESULTS: In the NORDynamIC trial, age < 40 years or achieving HCV RNA < 1000 IU/mL day 7 were highly predictive of favorable outcome following 12 weeks therapy. Among 255 Finnish real-life patients below the age of 40 years treated for 12 weeks with interferon and ribavirin, 87% of HCV genotype 2 and 79% of genotype 3 infected patients achieved SVR, and among 117 Swedish real-life patients treated for 12-16 weeks, 97% of HCV genotype 2 and 94% of genotype 3 infected achieved SVR. CONCLUSIONS: Short interferon-based therapy offers a high likelihood of achieving SVR for selected HCV genotype 2/3 infected patients, and is an acceptable option given that a thorough discussion of the side effects is provided prior to initiation.

Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3.

UNLABELLED: The present study evaluated the impact of variations in the inosine triphosphate pyrophosphatase (ITPase) gene (ITPA) on treatment outcome in patients with hepatitis C virus (HCV) genotype 2/3 infection receiving peginterferon-α2a and lower, conventional 800 mg daily dose of ribavirin. Previous studies using higher, weight-based ribavirin dosing report that patients carrying polymorphisms encoding reduced predicted ITPase activity show decreased risk of ribavirin-induced anemia but increased risk of thrombocytopenia, with no impact on elimination of virus. In all, 354 treatment-naïve HCV genotype 2/3-infected patients, enrolled in a phase III trial (NORDynamIC), were genotyped for ITPA (rs1127354 and rs7270101). Homo- or heterozygosity at Ars1127354 or Crs7270101 , entailing reduced ITPase activity, was observed in 37% of patients and was associated with increased likelihood of achieving sustained virological response (SVR) (P = 0.0003 in univariate and P = 0.0002 in multivariate analyses) accompanied by a reduced risk of relapse among treatment-adherent patients. The association between ITPA variants and SVR remained significant when patients were subdivided by the 12- and 24-week treatment duration arms, HCV genotype, fibrosis stage, and IL28B genotype, and was not secondary to improved adherence to therapy or less pronounced anemia. Gene variants predicting reduced predicted ITPase activity were also associated with decreased risk of anemia (P < 0.0001), increased risk of thrombocytopenia (P = 0.007), and lower ribavirin concentrations (P = 0.02). CONCLUSION: These findings demonstrate a novel ribavirin-like association between polymorphisms at ITPA and treatment efficacy in chronic hepatitis C mediated by reduced relapse risk. We hypothesize that patients (63%) being homozygous for both major alleles, leading to normal ITPase activity, may benefit more from the addition of ribavirin to present and future treatment regimens for HCV in spite of concomitant increased risk of anemia.

Norovirus GII.4 detection in environmental samples from patient rooms during nosocomial outbreaks.

Norovirus (NoV) is an important cause of nosocomial gastroenteric outbreaks. This 5-month study was designed to characterize NoV contamination and airborne dispersal in patient rooms during hospital outbreaks. Air vents, overbed tables, washbasins, dust, and virus traps designed to collect charged particles from the air were swabbed to investigate the possibility of NoV contamination in patient rooms during outbreaks in seven wards and in an outbreak-free ward. Symptomatic inpatients were also sampled. Nucleic acid extracts of the samples were examined for NoV RNA using genogroup I (GI) and GII real-time reverse transcription-PCR (RT-PCR). The NoV strains were characterized by RT-PCR, sequencing, and phylogenetic analysis of the RNA-dependent RNA-polymerase-N/S capsid-coding region (1,040 nucleotides [nt]). Patient strains from two outbreaks in one ward were sequenced across the RNA-dependent-RNA-polymerase major capsid-coding region (2.5 kb), including the hypervariable P2 domain. In the outbreak wards, NoV GII was detected in 48 of 101 (47%) environmental swabs and 63 of 108 patients (58%); NoV genotype II.4 was sequenced from 18 environmental samples, dust (n = 8), virus traps (n = 4), surfaces (n = 6), and 56 patients. In contrast, NoV GII was detected in 2 (GII.4) of 28 (7%) environmental samples and in 2 (GII.6 and GII.4) of 17 patients in the outbreak-free ward. Sequence analyses revealed a high degree of similarity (>99.5%, 1,040 nt) between NoV GII.4 environmental and patient strains from a given ward at a given time. The strains clustered on 11 subbranches of the phylogenetic tree, with strong correlations to time and place. The high nucleotide similarity between the NoV GII.4 strains from patients and their hospital room environment provided molecular evidence of GII.4 dispersal in the air and dust; therefore, interventional cleaning studies are justified.